Luspatercept (ACE-536) Increases Hemoglobin and Decreases - - PowerPoint PPT Presentation

▶
luspatercept ace 536 increases hemoglobin and decreases
SMART_READER_LITE
LIVE PREVIEW

Luspatercept (ACE-536) Increases Hemoglobin and Decreases - - PowerPoint PPT Presentation

Aug 20, 2023 1.02k likes •1.31k views

Luspatercept (ACE-536) Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study Antonio G Piga, MD 1 , Silverio Perrotta, MD 2 , Angela Melpignano, MD 3 ,

slide-1
SLIDE 1

Luspatercept (ACE-536) Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study

1Turin University, Italy; 2Second University of Naples; 3Ospedale "A. Perrino", Brindisi; 4University of

Ferrara, Italy; 5Laiko General Hospital, Athens, Greece; 6Garibaldi Hospital, Catania; 7AORN "A. Cardarelli", Naples, Italy; 8Ege University Children's Hospital, Izmir, Turkey; 9Acceleron Pharma, Cambridge, MA; 10Celgene Corporation, Summit, NJ, USA.

Antonio G Piga, MD1, Silverio Perrotta, MD2, Angela Melpignano, MD3, Caterina Borgna- Pignatti, MD4, M. Rita Gamberini4, Ersi Voskaridou, MD5, Vincenzo Caruso, MD6, Aldo Filosa, MD7, Yesim Aydinok, MD8, Carrie Condon9, Dawn M. Wilson9, Abderrahmane Laadem, MD10, Matthew L. Sherman, MD9 and Kenneth M. Attie, MD9

slide-2
SLIDE 2

Page 1

Disclosures – Dr. Antonio Piga

  • Research grant from Acceleron
  • Consultant honoraria from Celgene
  • Research grant from Novartis
  • Research grant from ApoPharma
slide-3
SLIDE 3

Page 2

β-Thalassemia

  • Most severe forms require regular RBC transfusions to manage complications
  • Iron overload can result in major organ damage, including heart and liver, and death
  • Life-long daily iron chelation therapy is often inadequate in preventing iron toxicity
  • There are currently no safe and effective alternatives to RBC transfusion

Rund D, Rachmilewitz E, NEJM 2005

  • β-thalassemia is an inherited anemia due to defective synthesis of the β-globin chains

– α-globin inclusion bodies contribute to ineffective erythropoiesis

slide-4
SLIDE 4

Page 3

  • Ineffective erythropoiesis is characterized by elevated TGF-β superfamily

ligands and Smad 2/3 signaling

  • Luspatercept is a recombinant fusion protein containing a modified

extracellular domain (ECD) of the activin receptor type IIB (ActRIIB)

  • Luspatercept binds to GDF11 and other ligands, inhibits Smad 2/3 signaling,

and promotes late-stage erythroid differentiation

Suragani R et al., Nature Med 2014

Background: Luspatercept (ACE-536)

Luspatercept Modified ECD of ActRIIB receptor Fc domain of human IgG1 antibody

Retic Baso E BFU-E CFU-E Pro E RBC Poly E Ortho E

Luspatercept EPO

slide-5
SLIDE 5

Page 4

RAP-536* Corrects Ineffective Erythropoiesis in β-Thalassemia Mouse Model (Hbb-/-)

Suragani R et al., Blood 2014

Increased RBC

wt bthal+TBS bthal+RAP-536

# # # p< 0.001 vs wt; ** p< 0.01 vs bthal + TBS

wt bthal+TBS bthal+RAP-536

Decreased Liver Iron Improved Bone Mineral Density

wt bthal+TBS bthal+RAP-536

Reduced Spleen Size

wt bthal+TBS bthal+RAP-536

Improved RBC Morphology

*RAP-536 is the murine analog of luspatercept

slide-6
SLIDE 6

Page 5

Luspatercept Treatment Period Screening Period Follow-up Period

Study Week

  • 4 BL 3 6

9 12 16 20

  • Treatment: Luspatercept administered subcutaneously every 3 weeks for 3 months:

Study Overview

Luspatercept β-Thalassemia Phase 2 Clinical Trial

NCT01749540, EudraCT 2012-002499-15

  • A phase 2, multicenter, open-label, dose escalation study in adults with β-thalassemia
  • Primary efficacy endpoints:
  • Non-transfusion dependent (NTD)*  Hb increase of ≥ 1.5 g/dL for ≥ 2 weeks
  • Transfusion dependent (TD)**  Transfusion burden decrease ≥ 20% over 12 weeks
  • Secondary endpoints:

– Safety and tolerability – PK – PD such as liver iron concentration, serum ferritin, and biomarkers of erythropoiesis

* NTD = <4 U/8 weeks, hemoglobin < 10 g/dL ** TD = ≥4 U/8 weeks confirmed over 6 months

slide-7
SLIDE 7

Page 6

Study Design

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Cohort 5

1.0 mg/kg (N=6)

Cohort 1

0.2 mg/kg (N=6)

Cohort 2

0.4 mg/kg (N=6)

Cohort 3

0.6 mg/kg (N=6)

Cohort 4

0.8 mg/kg (N=6)

3 Months Treatment

Completed

Data from completed cohorts presented Cohort 6 1.25 mg/kg (N=6) Expansion Cohort

Individually titrated dose (N=30)

Patients completing base study can enroll into a 12-month extension study

Active As of 1 Dec 2014

slide-8
SLIDE 8

Page 7

Baseline Characteristics

Luspatercept β-Thalassemia Phase 2 Clinical Trial All Patients N=30 Age, yr, median (range) 34.5 (20-57) Sex, male (%) 16 (53%) Splenectomy (%) 25 (83%) Non-Transfusion Dependent (NTD) N= 23 (77%) Hemoglobin, g/dL, mean ± SD 8.3 ± 0.9 Transfusion Dependent (TD) N=7 (23%) RBC Units/12 weeks, mean ± SD 7.3 ± 1.0

Data as of 10 Oct 2014

slide-9
SLIDE 9

Page 8

Safety Summary

Luspatercept β-Thalassemia Phase 2 Clinical Trial

  • No related serious adverse events

– 1 grade 3 dose-limiting toxicity (worsening lumbar spine bone pain)

  • 3 patients discontinued early associated with an AE

– 1 each with occipital headache, ankle pain, and back pain

Data as of 10 Oct 2014 Preferred Term 0.2 mg/kg (N = 6) 0.4 mg/kg (N = 6) 0.6 mg/kg (N = 6) 0.8 mg/kg (N = 6) 1.0 mg/kg (N = 6) Overall (N = 30) n (%) Bone pain 1 3 2 6 (20.0%) Headache 1 2 2 5 (16.7%) Myalgia 1 2 1 4 (13.3%) Asthenia 1 2 3 ( 10.0%) Influenza 2 2 ( 6.7%) Macule 2 2 ( 6.7%) Pain in Extremity 2 2 ( 6.7%)

Related Adverse Events in ≥5% Patients

  • No development of antidrug antibodies on treatment
slide-10
SLIDE 10

Non-Transfusion Dependent Patients

slide-11
SLIDE 11

Page 10

NTD, Non-transfusion dependent

Maximum Hemoglobin Increase in NTD Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Data as of 10 Oct 2014

slide-12
SLIDE 12

Page 11

Sustained Hemoglobin Increase in NTD Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Data as of 10 Oct 2014

  • Higher doses (0.8-1.0 mg/kg) produced sustained increases

in hemoglobin levels

0.2-0.6 mg/kg (N=17) n (%) 0.8-1.0 mg/kg (N=6) n (%) Hb increase ≥ 1.5 g/dL for ≥2 weeks (1° endpoint) 0 (0%) 3 (50%) Mean Hb increase ≥ 1.5 g/dL for ≥ 9 weeks 0 (0%) 2 (33%)

NTD, Non-transfusion dependent

slide-13
SLIDE 13

Page 12

NTD Responder Hemoglobin

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Data as of 10 Oct 2014 NTD, Non-transfusion dependent

Hemoglobin (g/dL) Weeks

1 2 3 4 5 6 7 8

6 7 8 9 10 11

  • 3

BL 3 6 9 12 16 20

Hemoglobin 0.8 mg/kg 24 year old male Splenectomized

Follow-up Period

slide-14
SLIDE 14

Page 13

Liver Iron Concentration (LIC by MRI) in NTD Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Data as of 10 Oct 2014

Baseline LIC ≥ 5 mg/g dry weight (dw) (n=12)

  • 8/12 patients had a decrease of ≥1 mg/g dw
  • 5
  • 4
  • 3
  • 2
  • 1

1 2 3

On iron chelator No iron chelator

Change from Baseline at 16 weeks in LIC (mg/g dw) Dose (mg/kg) 0.2 0.4 0.6 1.0

NTD, Non-transfusion dependent

slide-15
SLIDE 15

Transfusion Dependent Patients

slide-16
SLIDE 16

Page 15

Reduced Transfusion Burden in TD Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

  • 100
  • 80
  • 60
  • 40
  • 20
  • 79%
  • 67%
  • 70%
  • 75%
  • 63%
  • 67%
  • 100%
  • 7/7 (100%) patients had >60% reduction in transfusion burden over 12 weeks
  • Includes 2 patients with β0β0 genotype (79%, 75% reduction)

TD, Transfusion dependent Data as of 10 Oct 2014

% Change in Transfusion Burden

0.6 mg/kg 0.8 mg/kg 1.0 mg/kg

  • - - Protocol-defined threshold

*Based on 8 weeks data

*

slide-17
SLIDE 17

Page 16

TD Responder Hemoglobin

Luspatercept β-Thalassemia Phase 2 Clinical Trial

TD, Transfusion dependent Data as of 10 Oct 2014

Hemoglobin (g/dL) Weeks

2 2 2 1 2 6 7 8 9 10 11 12 13

  • 9
  • 6
  • 3

BL 3 6 9 12 16 20

Units Transfused Hemoglobin 1.0 mg/kg 40 year old male Splenectomized

Follow-up Period

  • 9
  • 6
  • 3

BL 3 6 9 12 16 20

slide-18
SLIDE 18

Page 17

Reduced Liver Iron Concentration (MRI) in TD Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Data as of 10 Oct 2014

Baseline LIC ≥ 5 mg/g dw (n=5)

Baseline LIC: 6.8 7.3 6.5 21.4 12.2

  • Max. % Decr. Ferritin:
  • 39.7
  • 27.5
  • 59.5
  • 26.5
  • 12.3

0.6 mg/kg 0.8 mg/kg 1.0 mg/kg

  • 6
  • 4
  • 2

2 4 6 Change from Baseline at 16 weeks in LIC (mg/g dw) Iron chelation therapy

slide-19
SLIDE 19

Page 18

Healing of Leg Ulcers in 2 of 2 Patients

Luspatercept β-Thalassemia Phase 2 Clinical Trial

Pre-Treatment After 6 Weeks Pre-Treatment After 4 Weeks After 18 Weeks

TD patient treated at 1.0 mg/kg NTD patient treated at 0.4 mg/kg

NTD, Non-transfusion dependent TD, Transfusion dependent

Data as of 10 Oct 2014

slide-20
SLIDE 20

Page 19

Conclusions

Luspatercept β-Thalassemia Phase 2 Clinical Trial

  • Luspatercept treatment of β-thalassemia patients for 3 months at dose levels of

0.8-1.0 mg/kg demonstrated 75% of patients met the primary efficacy endpoint – Increase in hemoglobin ≥ 1.5 g/dL for ≥ 2 weeks in 50% of NTD patients – Decrease in RBC transfusion burden > 60% in 100% of TD patients

  • Liver iron concentration and serum ferritin decreased in TD and NTD patients
  • Rapid healing of leg ulcers was observed in 2 of 2 patients
  • The safety profile was favorable with no related serious adverse events
  • These data strongly support further evaluation of luspatercept in patients with

β-thalassemia

slide-21
SLIDE 21

Page 20

Acknowledgments

Luspatercept β-Thalassemia Phase 2 Clinical Trial

  • Investigators: A Piga, A Melpignano, S Perrotta, C Borgna-Pignatti,

MR Gamberini, V Caruso, E Voskaridou, A Filosa, Y Aydinok

  • Sub-investigators: M Genisio, S Roggero, F Longo, F Della Rocca, U Pugliese,

I Tartaglione, L Manfredini, A Quarta, G Abbate, S Anastasi, R Lisi, M Casale, P Cinque, S Costantini, M Marsella, P Ricchi, A Spasiano

  • Acceleron: K Attie, M Sherman, D Wilson, C Condon, C Rovaldi, M Hankin,

B O‘Hare, T Akers, E Raptis-Zarou, S Ertel, T Sacco

  • Chiltern: C Lanza, F Van der Schueren, M Belfiore, M Notredame
  • Central Labs: CRL, ICON
  • Independent Safety Reviewer: E Neufeld
  • Sponsored by Acceleron and Celgene